13beta-carboxy-17beta-hydroxy-10beta-methylgon-4-en-3-one, derivatives thereof and intermediates thereto



United States Patent a 3,043,836 13fl-CARBOXY-17B-HYDROXY 4-EN-3-0NE, DERIVATIVES THEREOF AND IN- TERMEDIATES THERETO Raphael Pappo, Skokie, Ill., assignor to G. D. Searle &

C0., Chicago, 111., a corporation of Delaware N0 Drawing. Filed May 2, 1961, Ser. No. 107,043,

p v 12 Claims. (Ci. 260-43957) The present invention is concerned with novel steroids ofthegon-4-en-3-one series, and more particularly, with l3B-carboxy-l7fi-hydroxygon-4-en-3-one and derivatives thereof, as represented by the structural formulae and o=o-o wherein hydrogen or a lower alkyl radical. A further object of this invention is to provide novel interp METHYLGON- mediates useful in the manufacture of the compounds of the foregoing structural formulae. These intermediates are represented by the structural formulae and 3,43,836 Patented July 10, 1962 2 ample, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the branched-chain isomers thereof.

This application is a continuation-in-part of my copending application, Serial No. 41,732, filed July 11, 1960; and now abandoned.

' Starting materials suitable for the manufactureof the instant compounds are 18,20-epoxy-20-hyroxypregn-4-en- 3-one and"18,20-epoxypregna-4,20-dien-3-one. Treatment of either of the latter substances with hydrogen peroxide in a suitables-olvent medium in the presence of an acid catalyst results in l8,20-epoxypregn-4-en-3-one ZO-hydroperoxide. Treatment of this hydroperoxide with methanesulfonyl chloride produces 18-acetoxy-l7a-chloroandrost-4-en-3-one. Treatment of the latter chloro compound with lithium chloride results in the instant 18-acetoxy-l7B-chloroandrost-4-en-3-one While reaction with lithium bromide or lithium iodide affords the 170cand 17pisomers of 18-acetoxy- 17-bromoandrost-4-en-3 -one and 18+acetoxy-17 -iodoandrost-4 -en3-one, respectively. Reaction of. the aforementioned 17a-chloro compound with silver fluoride produces the 17ocand 17,8- stereoisomers of 18-acetoxy-l7-fiuoroandrost 4-en-3-one. An alternate process particularly suitable for the manufacture of the instant 17-iodo. compounds involves conversion of the aforementioned 18,20-epoxypregn-4-en-3-one 20-hydroperoxide to the corresponding acetate-by treatment with acetic anhydride in pyridine. Reaction of this acetate with sodium iodide, preferably in the presence of triethylamine, affords 18-acetoxy-l7a-iodoandrost-4-en-3- one.

Mild hydrolysis of the aforementioned 18-acetoxy-17- haloandrost:4-en-3-ones results in the corresponding 17- halo-18-hydroxy compounds. Typically, 18-acetoxy-17uchloroandrost-4-en-3-one is treated with p-toluene-sulfonic acid in aqueous methanol to produce 17u-chloro- 18-hydroxyandrost-4-en-3-one. Acylation of these 18- hydroxy compounds affords the corresponding l8-(lower alkanoates) as is exemplified by reaction of the latter 17a-chloro-l8-hydroxyandrost-4-en-3-one with propionic anhydride in pyridine to yield l7a-chloro-l8-propionoxyandrost-4-en-3-one. Oxidation of the aforementioned 17-ha1o-18- hydroxy compounds with a limited quantity of oxidizing agent results in the corresponding l8-oxo compounds, while the use of excess oxidant affords the -l3/3-carbo'xy derivatives. These processes are specifically illustrated by the reaction of l7a-chloro-l8-hydroxyandrost-4-en-3-one with one .molecular equivalent of aqueous chromic acid to produce 17a-chloro-l8-oxoandrost-4-en-3-one, or with slightly more than two molecular equivalents of that reagent to afiord 13B-carboxy- 17a-chloro-lOfi-methylgori-4-en-3-one. Reaction of these "13fi-carboxy compounds with-a diazoalkane' afiords the corresponding l3fl-carbalk'oxy compounds as is illustrated by the preparation 'of 13fi-carbomethoxy-l7u-chloro-10B- methylgon-4-en-3-one by the reaction of l3l8-carboxy-l7achloro-l0l8-methylgon-4 en-3-one with diazomethane in ether.

The instant 13/3 carboxy-17fi-hydroxy-lOfi-methylgon- 4-en-3-one lactone is obtained by treatment of the corresponding 17-halo compounds described supra with aqueous alkali. As a specific example, 13,8-carboxy-l7achloro-l0,B-methylgon-4 en-37one is allowed to react with aqueous sodium hydroxide and ether to produce the latter lacetone. Further reaction of this lactone with aqueous sodium hydroxide followed by acidification with dilute. hydrochloric acid produces the hydroxy-acid, 13/3- carboxy 17/3 hydroxy lOfl methylgon 4 en 3- one. This hydroxy-acid is converted to the instant 13B- carbalkoxy-l7fi-hydroxy compounds by reaction with the appropriate diazoalkane. For example, a solution of carboxy 17/3 hydroxy 10B methylgon 4 en- 3-one in methanol is allowed to react with ethereal unless otherwise noted.

anti-hormonal agents as evidenced by their ability to inhibit the sodium-retaining activity ofydesoxycorticosten one actate. In addition, as is described supra, the instant- 17-halov compounds are useful as intermediates in the manufacture of the, 17-oxygenated Compounds of this invention.

The invention will appear more fully from the exam-; ples which follow These examples are set forth by way of illustration only and it will be understood that the invention is not to be construed as limited in spirit or in scope by the details contained therein, as many modifications in materials and methods will be apparent from this disclosure to those skilled in the art. In these examples temperatures are given in degrees centigrade C.) and quantities of materialsin parts by weight,

Example Method A.--A solution of 12.4 parts of 18,20-epoxy- 20-hydroxypregna4-en-3-one in 270 parts" of warm benzene is cooled janddiluted with 360 parts of ether. The mixture is cooled to about then treated successively with parts of 90% aqueous hydrogen peroxide and 0.28 part of p-toluenesulfonic acid monohydrate. Stirring is continued forabout one hour at 5.- sulting precipitate is collected by filtration, washed with ether, and dried to afiord" 18,20-epoxypregn-4-en-3-one ZO-hydroperoxide, M.P. 185-190 (dec.)'. It displays in frard maxima at 3.60, 6.0, and 11.5 microns;

The re- Method B.The substitution of an equivalent quail tity of 18,20-epoxypregna-4,20-dien-3-one' for 18,20- epoxy:-hydroxypregn-4-en-3-one in, the process describedunder Method A results also in 18,20-epoxypregn- 4-en-3-one 20-hydroperoxide.

Method C.--To a solution of 50.56 parts of 18,20- epoxy-ZO-hydroxypregn-4-en-3-one in 567 parts of warm dioxane is added 098- part of p-toluenesulfonic acid monohydrate. The resulting mixture is'cooled to room temperature, then treated with 111.2 parts of aqueoushydrogen peroxide over a period of aboutZ minutes. Stirring is continued for about one hour at 0-5"; and the resulting precipitate is collected by filtratiom washed successively with dioxane and ether, and dried to afiord 18,20-epoxypregn-4-en-3-one ZO-hydroperoxide, identical with the product obtained by the'procedure of Method Asupra.

Example 2 To a solution of 14.8 parts of methanesulfonyl chloride in 55 parts of anhydrous pyridine, cooled to 0-5", is

added 553 parts of 18,20-epoxypregn-4-en-3bne 2'0-hy- 65 droperoxide. I The reaction mixture is stirred until homo.- geneity is achieved, allowedto stand at 5 for about 4 hours, then treated successively with ice andether. The resulting mixture is extracted with an ether-benzene solution and the organic extract is washed successively with hydrochloric acid, water, aqueous sodium hydroxide, and water; dried over anhydrous sodium sulfate, and evaporated to dryness at reduced pressure. The residue is dissolved in benzene and adsorbed on silica gel.v

The chromatographic column is eluted with 20% other in benzene to afford 18-acetoxy-17a-chloroandrost-4-en- 3-one, which exhibits maxima in the infrared at 3.4, 5.75, 6.0, 7.23, 8.0, and 9.65 microns.

' Example 3 .mixture of 5.07 parts of 18-acetoxy-17ot-chloroandrost-4-en-3rone, 5 parts of p-toluenesulfonic acid monohydrate, 400 pants of methanol, and 20 parts of layer separated, washed successively with aqueous P tassium bicarbonate and water, dried over anhydrous sodium sulfate, and concentrated to afford a crystalline residue. Recrystallization from benzene afiords pure 17ccchloro 18 hydroxyandrost 4 en 3 one, M.P.205-21 0 (dec.). 7

Example 4 A mixture of one part of 17a-chloro-18-hydroxyandrost-4-en-3-one, 13 parts of propionic anhydride, and 20 parts of pyridine is allowed to stand at room temperature for about 16 hours, then diluted with water and extracted with benzene. V The benzene solution is washed successively with dilute hydrochloric acid and water, dried over anhydrous sodium sulfate, and evaporated to dry ness in vacuo to afford 17achloro-18-propionoxy-androst 4-en-3-one.

Example 5 To a solution of one 'part of 17a-chloro-1'8-hydroxyandrost-4-en-3-one in parts of acetone is added 2 parts by volume of an aqueous solution, 8 N in chromium trioxide and 8 N in sulfuric acid. The mixture is stirred at room temperature for about one hour, treated with 0.5 part of isopropanol, and concentrated to a small volume at room temperature, under nitrogen. The residue is extracted with benzene -andthe benzene extract 7 washed with Water, dried over anhydrous sodium sul-.

fate, and evaporated to dryness under reduced pressure. The solid residue is crystallized from ether to yield pure 13 3 carboxy 17a chloro 1'05 methylgon 4 en- 3-one, M.P. 214-220 (dec.).

Example 6 To a solution of 1.06 parts of 17u-chloro-18-hydroxyandrost-4-en-3-one in 120 parts of acetone is added dropvvise, 1.4 parts by volume of an aqueous solution, 8 N in chromium trioxide and 8 N in sulfuric acid, and the mixture is stirred at room temperature for about 5 minutes. A few drops of isopropanol are added to destroy the excess chromium trioxide and the mixture is evaporated toa small volume in vacuo. The residue is extracted with benzene and this extract washed successively with aqueous sodium hydroxide and water, dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo. Tri-' turation of the residue with other results in crystallization of pure 17a-chloro-18-oxoandrost-4-en-3-one, M.P. 112-125".

Example 7 Example 8 A mixture of 2.334 parts of 18,20'-epoxypregn-4-en-3- one 20-hydroperoxide, 12 parts of pyridine, and 5 parts of acetic anhydride is stirred until the mixture becomes homogeneous. It is stored at room temperature for about 1 /2 hours, then at 0-5 for about 15 hours, and stirred and treated with about 20 parts of ice. The resulting crystalline precipitate is collected by-fil-tration, washed successively with ice-cold aqueous pyridine and water, then extracted with ethersbenzene. The organic layer is separated, Washed successively with water, aqueous sodium hydroxide and water, dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo to produce a crystalline residue. Recrystallization of this residue from acetone-ether afiords small prisms of 18,20- epoxypregn-4-en-3-one 20-hydroperoxide acetate, M.P. about-110-114 (dec.).

Example 9 A mixture of 2 parts of 18,20-epoxypregn-4-en-3-one ZO-hydroperoxide acetate, 11.2 parts of acetone, 0.9 part of triethylamine, 4 parts of dried sodium iodide, and 0.2 part of Water is stirred at room temperature for about 6 hours, then diluted with benzene. The diluted mixture is washer successively with Water, aqueous sodium bisulfite, aqueous sodium hydroxide, aqueous hydrochloric acid, and water, then dried over anhydrous sodium sulfate. The solvent is removed by distillation at reduced pressure, and the resulting residue is chromatographed on silica gel. Elution with 10% ether in benzene produces crude 18-acetoXy-t17a-iodoandrost-4-en-3- one. Recrystallization of the crude product from ether results in the pure material, M.P. about 158-160". Further recrystallization from ethanol aifords material melting at about 1595-1605 3 Example 10 To a mixture of one part of anhydrous lithium bromide and 20 parts of ice-cold pyridine is added successively a solution of 3 parts of methanesulfonic' anhydride in 13.3 parts of dry tetrahydrofuran and a solution of one part of l8,20-epoxypregn-4-en-3-one ZO-hydroperoxide in 20 parts of pyridine. The addition of the latter solution is conducted at about -5 with stirring. The reaction mixture is stirred for about hours at 0-5", then is treated with ice and stirred for about one hour longer. This aqueous mixture is extracted with ether-benzene, and the organic layer is separated, Washed successively with dilute hydrochloric acid, water, and aqueous sodium hydroxide, then dried over anhydrous sodium sulfate. The solvent is distilled under reduced pressure, and the gummy residue is dissolved in benzene. Chromatography of the benzene solution on silica gel followed by elution of the column with ether in benzene affords 18-acetoxy-17a-bromoandrost-4-en-3-one as an oil. This substance displays infrared absorption maxima at about 5.75 and 6.0 microns.

Example 11 To a solution of 5 parts of l8-acetoxy-17a-iodoandrost- 4-en-3-one in 400 parts of methanol containing 20' parts of water is added 5 parts of p-toluenesulfonic acid, and this mixture is stored at room temperature for about 48 hours, then diluted with about 100 parts of water, and concentrated at reduced pressure. The residual solution is extracted with benzene, and the organic layer is separated, washed successively with water, aqueous potassium bicarbonate and water, then dried over anhydrous sodium sulfate. Concentration of the organic solution to dryness affords a residue, which is crystallized from ether to produce 1S-hydroxy-17a-iodoandrost-4-en-3-one. Further recrystallization from alcohol aifords prisms of the pure product, M.P. about 156-161 (dec.).

Example 12 To a solution of 2.7 parts of IB hYdfOXY-l'loc-iOdO- andost-4-en-3-one in 400 parts of acetone is added 6.5 parts by volume of an aqueous solution, 8 N in chromium trioxide and 8 N in sulfuric acid. The addition is carried out at room temperature over a period of about 10 minutes. Approximately 0.1 part of isopropyl alcohol is added to destroy the excess reagent, and the mixture is then concentrated to a small volume under nitrogen. The resulting solution is extracted with benzene, and the benzene extract is washed with water, then concentrated to dryness under reduced pressure. The resulting residue is triturated with ether to produce 17a-i0d0-18-0X0- androst-4-en-3-one.

The ethereal mother liquor is chromatographed on silica 6 gel. Elution of the column with 50% ether in benzene and with pure etherafiords 13p-carboxy-lfla-iodo-l0fimethylg on-4-en-3-one. I Q

The crude *17a-iodo-l8-oxoandrost-4-en-3-one is dissolved in benzene-ether, then washed with dilute aqueous sodium hydroxide? Concentration of the organic layer to dryness under reduced pressure, and recrystallization of the resulting residue from isopropyl alcohol produces the pure aldehyde, M.P. about 159-163.

Example 13 A suspension of 9.4 parts of 13fl-carboxy-17a-chloro- 10B-methylgon-4-en-3-one in 100 parts of aqueous sodium hydroxide, at pH 9-10, is shaken with 140 parts of ether. The ether layer is separated and evaporated to dryness to afford a crystalline residue, which is triturated with ether, resulting in 13fi-carboxy-17f3-hydroxy-10B-methylgon-4-en-3-one lactone, M.P. about 161-170. Recrystal- 'lization from benzene-methylcyclohexane yields small prisms, M.P. about l67-l77 (dec.). Infrared maxima are observed at about 5.55, 6.00, and 6.20 microns.

Example 14 The mother liquors from Example 13 are evaporated to dryness and the residue is dissolved in 160 parts of isopropyl alcohol. To the resulting solution is added 50 parts of 5% aqueous sodium hydroxide, and this mixture is allowed to stand at room temperature for about one hour, then diluted with water and extracted with benzene.

The organic layer is evaporated to dryness, and the resulting residue is crystallized from benzene-hexane to aflorded l0fl-methylgona-4,l3 (17)-dien-3-one, M.P. about 117- 121. Recrystallization from methanol affords material, melting at about 120-123. It displays maxima in the infrared at about 3.28, 6.00 and 6.20 microns.

Example 15 The aqueous alkaline solutions from Examples 13 and 14 are combined and acidified to pH 4 by the addition of dilute hydrochloric acid. The resulting cloudy suspension is extracted with chloroform, and the organic layer is washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness to yield 13,8-carboxy-17phydroxy-10B-methylgon-4-en-3 one, which exhibits infrared maxima at about 2.8-3.0, 5.85, 6.00, and 6.20 microns.

Example 16 wherein R is selected from the group consisting of hydrogen and-"lower alkyl radicals;

one.

3. 13 8-carboxy-17fl-hydroxy-10,8-methy1gon-4 en 3- one'lactone. i t

i 4. A member. selected from the :gronp consisting of compounds of the structural formulae 20 9. 18-acetoXy-17a-iodoandrost-4-en-3-one.

10. 18-hydroxy-17a-iodoandrost-4-en-3-one. 1 1. 17 a-iodo-l 8-oxoandrost-4-en-3-one. 12. 13fl-carboxy-17a-iodo-10B-methy1gon-4-en-3-one.

7 No references cited. 25

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,043 836 July 1O 1962 Raphael Pappo It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, line 70, for "isometers" read isomers column 2, line 64, for "lacetone" read lactone column 3 line 33, for "3.60" read 3.0 column 4, line 16, for "propionoxy-androst" read propionoxyandrost column 6, lines 32 and 33, for "afforded" read afford column 7, lines 12 to 23, the formula should appear as shown below instead of as in the patent:

I Y H C Signed and sealed this 30th day of July 1963.

(SEAL) Attest:

ERNEST W. SWIDER DAVID L. LADD Attesting Officer Commissioner of Patents 

3. 13B-CARBOXY-1MB-HYDROXY-10B-METHYLGON-4 - EN - 3 ONE LACTONE. 